Sodium proton exchangers (NHEs) constitute a large family of polytopic membrane protein transporters found in organisms across all domains of life. They work by exchanging extracellular sodium or lithium ions for intracellular protons. In animal cells, they are linked to a variety of physiological roles with the most important being regulation of intracellular pH and cell volume. To date nine isoforms (NHE1-9) have been identified in the human NHE family. The Na+/H+ exchanger isoform 1 (NHE-1) has a multitude of important and specific tasks and its basic role of maintaining intracellular pH and cell volume affect cell growth, proliferation, migration and apoptosis, and plays important roles in heart disease and cancer. The transporter protein consists of 12 transmembrane (TM) segments with the amino and carboxyl termini of the protein both being located on the cytoplasmic side, although recently, there is some controversy on the fundamental structure of the protein.
Genepin (Axon 1443) is an excellent natural cross-linker for proteins, collagen, gelatin, and chitosan. Besides, it has been shown to inhibit uncoupling protein 2 (UCP2), is a mitochondrial carrier protein that negatively regulates insuline secretion by inhibiting UCP2 mediated proton leak. As UCP2 is an important mediator of β-cell dysfunction, it has been hypothesized that UCP2 inhibitors lacking adverse side effects could be useful drugs for treatment of β-cell dysfunction and type 2 diabetes. Other functions addressed to UCP2 are the suppression of production of mitochondrial reactive oxygen species (ROS) and the ability to mitigate oxidative stress in drug-resistant cancer cells.
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 C.Y. Zhang et al. Genipin inhibitsUCP2-mediated proton leak and acutely reverses obesity- and high glucose-induced beta cell dysfunction in isolated pancreatic islets. Cell. Metab. 2006, 3, 417-427.
 R.J. Mailloux et al. Genipin-Induced Inhibition of Uncoupling Protein-2 Sensitizes Drug-Resistant Cancer Cells to Cytotoxic Agents. PLoS One. 2010, 5, e13289.